Role of protein-protein interactions in the antiapoptotic function of EWS-Fli-1.

In the majority of Ewing's family tumors, chromosomal translocation t(11;22) leads to aberrant fusion of RNA-binding protein EWS with DNA-binding ETS transcriptional factor Fli-1. EWS-Fli-1 has altered the transcriptional activity and modulating its downstream target genes through this transcriptional activity is thought to be responsible for this tumor. We have previously shown that both EWS-Fli-1 and Fli-1 have antiapoptotic activity against several apoptotic inducers. Here, we show that the transcriptional activity of EWS-Fli-1 and Fli-1 is not essential for its antiapoptotic activity. We also demonstrate that EWS-Fli-1 and Fli-1 interact with CBP through its amino-terminal region and inhibit the CBP-dependent transcriptional activity of RXR. This activity appears to be independent of DNA-binding activity of EWS-Fli-1. Introduction of the dominant-negative form of CBP into Ewing's sarcoma cells sensitizes these cells against genotoxic or retinoic-acid induced apoptosis. These results suggest that the ability of EWS-Fli-1/Fli-1 to target transcriptional cofactor(s) and modulate apoptotic pathways may be responsible for its antiapoptotic and tumorigenic activities.
AuthorsRamugounder Ramakrishnan, Yasuo Fujimura, Jian Ping Zou, Fang Liu, Leo Lee, Veena N Rao, E Shyam P Reddy
JournalOncogene (Oncogene) Vol. 23 Issue 42 Pg. 7087-94 (Sep 16 2004) ISSN: 0950-9232 [Print] England
PMID15273724 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Actins
  • DNA Primers
  • FLII protein, human
  • Gelsolin
  • Microfilament Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Actins (genetics)
  • Apoptosis (physiology)
  • Base Sequence
  • Bone Neoplasms (genetics)
  • Cell Survival (physiology)
  • Chromosomes, Human, Pair 11 (genetics)
  • Chromosomes, Human, Pair 22 (genetics)
  • DNA Primers
  • Gelsolin (genetics, pharmacology)
  • Humans
  • Microfilament Proteins
  • Polymerase Chain Reaction (methods)
  • Receptors, Cytoplasmic and Nuclear (genetics)
  • Sarcoma, Ewing (genetics)
  • Transcription, Genetic
  • Transfection
  • Translocation, Genetic

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